Sulfur mustard, a potent chemical warfare vesicant, is considered to be a high priority chemical threat. Although it has been studied for more than 80 years, the mechanisms mediating its actions as a vesicant remain unknown; moreover, to date, there are no effective medical countermeasures for exposure to warfare vesicants. The proposed UMDNJ/Rutgers University CounterACT Research Center of Excellence will specifically focus on the development of drugs to treat sulfur mustard poisoning. In collaborative studies with a local pharmaceutical company and Battelle Memorial Institute, we have identified two candidate classes of Pharmaceuticals that can prevent or reverse sulfur mustard toxicity. At least one member of each class of drugs has previously been approved by the FDA for other indications. In this academic/industrial partnership, plans are to optimize the lead compounds from the groups we have identified, to determine the active pharmacophores, and ultimately to synthesize structural isomers. We will also evaluate the efficacy of these potential countermeasures in model systems of sulfur mustard toxicity. In addition, Research and Development Projects are proposed that are designed to identify specific mechanisms of action of sulfur mustard and potential new targets for therapeutic intervention in three major vesicant targets: the eye, the skin and the lung. Investigators on these projects will work closely with a Pharmacology and Drug Development Core and a Medicinal Chemistry and Pharmaceutics Core with considerable expertise in drug development, providing insights to facilitate the development of sulfur mustard countermeasures. The research laboratories of the PI, co-Pi, Pi's of the Research and Development Projects, the Pharmaceutics group and Pharmacology and Drug Development Core are located in close proximity to one another on the Busch campus of Rutgers University. They are all members of the Environmental and Occupational Health Sciences Institute (EOHSI), a facility jointly sponsored by UMDNJ-Robert Wood Johnson Medical School and the School of Pharmacy at Rutgers University. EOHSI has been designated as an NIEHS Center of Excellence. The Medicinal Chemistry group is located at Lehigh University, approximately 25 miles from Rutgers University. The P.I. of this Center (J. Laskin) and the P.I. of the Medicinal Chemistry Core (N. Heindel) have been jointly funded by NIEHS on drug development grants for over 15 years. A Training and Education Program is proposed that will be directed at health care providers at Rutgers University School of Pharmacy, UMDNJ-School of Public Health, UMDNJ-Robert Wood Johnson Medical School and the Health Sciences Program at Lehigh University.